CYTOKINES

SUMIT KUMAR

Cytokines

Cyto- cell kines – movement(greek)

A group of low molecular weight soluble

polypeptides or proteins which are

secreted by activated immunocytes or some

matrix cells and possess high activity and

various functions (mediate & regulate

immune responses and inflammatory

reactions).

Classification of cytokinesInterleukin(IL)

Interferon (IFN)

Tumor necrosis factor(TNF)

Chemokines(CK)

Colony stimulating factor(CSF)

Transforming growth factor(TGF)

NomenclatureInterleukins - that act as mediators between leukocytes. The vast

majority of these are produced by T-helper cells.

Lymphokines - produced by lymphocytes.

Monokines - produced exclusively by monocytes.

Interferons - involved in antiviral responses.

Colony Stimulating Factors - support the growth of cells in semi-

solid media.

Chemokines - mediate chemoattraction (chemotaxis) between

cells.

PROPERTIES1. Mostly low molecular weight small

polypeptides or glycoprotein(8~80 KD), and

most of them are monomer.

2.Natural cytokines are secreted by activated cells such as

activated immune cells, matrix cells and some tumor cells.

Mostly Cytokines are not stored inside cells (exceptions

are, for example TGF-β and PDGF which are stored in

platelets.)

3.Effects of cytokines :

Pleiotropism refers to the ability of one cytokine having

multiple effects on diverse cell types

Redundancy refers to the property of multiple cytokines

having the same or overlapping functional effects

Synergy refers to the property of two or more cytokines

having greater than additive effects.

Antagonism refers to the ability of one cytokine inhibiting

the action of another.

4.Cytokines initiate their actions by binding to

specific membrane receptors on target cells.

5.Only small quantities of cytokines are needed

to occupy receptors and elicit biologic effects.

6.Cytokines act on target cells by the 3 way :

Autocrine - Cytokine binds to receptor on same

cell that secreted it.

Paracrine -Cytokine binds to receptors on near

by cell.

Endocrine - Cytokine binds cells in distant parts

of the body after being carried in blood or tissue

fluids.

Distance

autocrine

endocrine

Blood circulation

paracrine Nearby

self

Cytokine -mediated effects

Cell growth

Cell differentiation

Cell death

Induce non-responsiveness to other cytokines/cells

Induce responsiveness to other cytokines/cells

Induce secretion of other Cytokines(Cascade Effect)

Th

Proinflammatory Cytokines TNF, IL-1, IL-6 , Chemokines (mostly)

Anti-inflammatory Cytokines IL-4,IL-10 ,IL-13, TGF-β, IL-1 ra

Antiviral Cytokines IFN-α,IFN-β,

Macrophages Activating Cytokines IFN-γ

B-cell Activating Cytokines IL-4, IL-5,IL-6, IL-21

T- Cell Activating Cytokines IFN-γ, IL-2, IL-4 , IL-12

Eosinophil And / Or Mast Cell Activating Cytokines

IL-3, IL-4, IL-5, IL-13

Types of cells producing Cytokines

Fibroblasts Reticulum Cells Macrophages

T- Cells Bone Marrow Stromal Cells

B – Cells Neutrophils

Natural Killer Cells Basophils

EosinophilsEndothelial Cells

Kidney Cells Liver Cells

Interleukins(IL)

Cytokines secreted by leukocytes that have the ability to act as signal molecules between different population of leukocytes.Eg.IL-1 –IL22

Interferon (IFN)

A group of glycoproteins that produced by

human or animal cells following the infection of

virus and exposure to various inducing agents.

Types:Type I- IFN-α , IFN-β, IFN- ω, bind to a specificcell surface receptor complex known as the IFNα receptor (IFNAR) that consistsof IFNAR1 and IFNAR2 chains.Type II- IFN-γ, Binds to IFNGR that consistsof IFNGR1 and IFNGR2 chainsType III- Signal through a receptor complexconsisting of IL10R2 (also called CRF2-4)and IFNLR1 (also called CRF2-12).

Chemokines(CK)

Cytokines which recruiting monocytes, granulocytes and lymphocytes in blood to the sites of inflammation & act through G-PCR.Types:CXC chemokines(α subgroup):IL-8 (Acute inflammation)CC chemokines(β subgroup):MCP-1, RANTES (Chronic inflammation)C chemokines(γ subgroup): Lymphotactin

CX3C chemokines(δ subgroup)*C: cysteine; X: any amino acid

Tumor necrosis

factor (TNF)

Refers to a group of cytokines that can cause cell

death (apoptosis).

Types:

TNF- produced mainly by activated monocytes

and macrophages, implicated in tumor

regression, septic shock, and cachexia.

TNF- (lymphotoxin alpha, LT-α) is produced

mainly by activated Th0 and Th1, inhibited

by interleukin 10. Lymphotoxin-alpha (LT-alpha)

and lymphotoxin-beta (LT-beta), two related

cytokines produced by lymphocytes that are

cytotoxic for a wide range of tumor cells in vitro

and in vivo.

Colony-stimulating factors

(CSF)

Colony-stimulating factors (CSFs) are secreted

glycoproteins that bind to receptor proteins on the

surfaces of hemopoietic stem cells , stimulate

proliferation and\or differentiation of pluripotent

hematopoietic stem cell and different progenitors

(Stimulate hematopoiesis )

Includes:

MCSF-Macrophage colony-stimulating factor

GMCSF-Granulocyte macrophage colony

stimulating factors.

GCSF-Granulocyte colony-stimulating factorsSCF-Stem cell factorEPO-ErythropoietinMulti-CSF (IL-3, IL-7)- growth of lymphocyte progenitor cells.

Transforming growth factor

(TGF)

Transforming growth-factor are cytokines whichstimulate the growth of their target cells.

Include: Transforming growth factor-(TGF- )

Epithelial growth factor(EGF)

Vascular endothelial cell growth factor(VEGF)

Fibroblastic growth factor(FGF)

Therapeutic Uses of Cytokines1.Interferon(IFN) in treatment of viral diseases, cancer.

Eg. IFN- treatment of condylomata acuminata (venereal or genital

warts), malignant melanoma, hairy cell leukemia and hepatitis B and C,

and other types of cancer including skin, kidney and bone cancers.

IFN-β- multiple sclerosis

IFN- -Chronic granulomatous disease in conjuction with other

antibacterial drugs

2.Cytokines are used to enhance T-cell activation in immunodeficiency

diseases, Eg. IL- 2, IFN-(Induction of Th 1 response),TNF-3. GM-CSF & G-CSF) induces increase in white cell count, it is used:

a- To restore leukocytic count after cytotoxic chemotherapy inducedneutropenia

b- After bone marrow transplantationC- To correct AIDS-associated leukopenia

Eg. G-CSF-Filgrastim, used to treat neutropenia in cancer patients.

GM-CSF-Sargramostim- used to treat neutropenia and fungal infections

in cancer patients.

4.Erythropoietin (EPO)-In Treatment of anemia of chronic renal

disease , in cancer patients on chemotherapy

5. Interleukin 2 (IL2)- Used to treat cancer

Eg:Aldesleukin -treatment of renal cell carcinoma, metastatic

melanoma & non-Hodgkin’s lymphoma (NHL).

6.Anakinra-IL-1 receptor antagonist used in treatment of severely

active rheumatoid arthritis . It reduces inflammation, decreases bone

and cartilage damage.

7. Etanercept- TNF- receptor agonist, treatment of rheumatoid

arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis and

psoriatic arthritis

8. IL-11 stimulate Platelet production, used in treatment of

thrombocytopenia caused by myelosuppressive agents.

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